The liver is unique in its capacity to regenerate after resection or massive injury to restore original parenchymal mass, structure and function. Regeneration of the liver after resection or major injury is dependent upon a highly regulated sequence of molecular and cellular events. Cytokines and growth factors are known to serve as important signals controlling initiation and progression of hepatocyte proliferation and replicatio as well as termination of this process once liver mass has been restored. Hepatic ischemia/reperfusion, as occurs from liver transplantation, resectional surgery or liver trauma, involves a prominent inflammatory response that contributes significantly to parenchymal damage and organ dysfunction. CXC chemokines are a class of small peptide mediators that promote inflammation by facilitating the recruitment of neutrophils to the liver. These neutrophils are a significant source of hepatocellular injury after ischemia/reperfusion. During the previous award, we discovered novel functions of CXC chemokines, acting through the receptors CXCR1 and CXCR2 on hepatocytes, to regulate hepatocyte proliferation and liver repair after ischemia/reperfusion. The current proposal builds on these data, and more recent findings that CXC chemokine receptors regulate the production and release of exosomes by hepatocytes and that these exosomes can directly alter hepatocyte proliferation and liver repair. Thus, the global hypothesis of this proposal is that the release of exosomes by hepatocytes is critical for liver repair and regeneration after ischemia/reperfusion injury and that CXCR1 and CXCR2 directly regulate the release of exosomes. In addition, we hypothesize that the contents of the exosomes, specifically components of the sphingolipid synthesis pathway and microRNA, are the mediators of the proliferative effects and promote liver repair and regeneration. The studies outlined in this proposal will: 1) determine how CXCR1 and CXCR2 regulate the nature and release of exosomes; and 2) determine how exosomes modulate liver repair and regeneration. These studies will provide important new information that will lead to new therapeutic approaches that could have significant impact on the treatment of acute liver injury that results from a number of liver diseases/disorders, trauma, surgery, or transplantation.